Discovery, Characterization and Comparison of Inhibitors of Bacillus Anthracis and Staphylococcus Aureus Replicative DNA Helicases

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2009 May 30

PMID 19477652

Citations 16

Authors

Daniel Aiello

Marjorie H Barnes

Esther E Biswas

Subhasis B Biswas

Shen Gu

John D Williams

Terry L Bowlin

Donald T Moir

Affiliations

Soon will be listed here.

Abstract

Antibacterial compounds with new mechanisms of action are needed for effective therapy against drug-resistant pathogens in the clinic and in biodefense. Screens for inhibitors of the essential replicative helicases of Bacillus anthracis and Staphylococcus aureus yielded 18 confirmed hits (IC(50)25 microM). Several (5 of 18) of the inhibitors were also shown to inhibit DNA replication in permeabilized polA-deficient B. anthracis cells. One of the most potent inhibitors also displayed antibacterial activity (MIC approximately 5 microg/ml against a range of Gram-positive species including bacilli and staphylococci) together with good selectivity for bacterial versus mammalian cells (CC(50)/MIC>16) suitable for further optimization. This compound shares the bicyclic ring of the clinically proven aminocoumarin scaffold, but is not a gyrase inhibitor. It exhibits a mixed mode of helicase inhibition including a component of competitive inhibition with the DNA substrate (K(i)=8 microM) and is rapidly bactericidal at 4 x MIC.

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References

Zhang Y, Yang F, Kurilla M, Pompliano D, Dicker I . Homogenous assays for Escherichia coli DnaB-stimulated DnaG primase and DnaB helicase and their use in screening for chemical inhibitors. Anal Biochem. 2002; 304(2):174-9. DOI: 10.1006/abio.2002.5627. View

Payne D, Gwynn M, Holmes D, Pompliano D . Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2006; 6(1):29-40. DOI: 10.1038/nrd2201. View

Schepetkin I, Khlebnikov A, Kirpotina L, Quinn M . Novel small-molecule inhibitors of anthrax lethal factor identified by high-throughput screening. J Med Chem. 2006; 49(17):5232-44. DOI: 10.1021/jm0605132. View

Sugino A, Higgins N, Brown P, Peebles C, Cozzarelli N . Energy coupling in DNA gyrase and the mechanism of action of novobiocin. Proc Natl Acad Sci U S A. 1978; 75(10):4838-42. PMC: 336216. DOI: 10.1073/pnas.75.10.4838. View

Saiki A, Shen L, Chen C, Baranowski J, Lerner C . DNA cleavage activities of Staphylococcus aureus gyrase and topoisomerase IV stimulated by quinolones and 2-pyridones. Antimicrob Agents Chemother. 1999; 43(7):1574-7. PMC: 89326. DOI: 10.1128/AAC.43.7.1574. View

Jiang S, Lu H, Liu S, Zhao Q, He Y, Debnath A . N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. Antimicrob Agents Chemother. 2004; 48(11):4349-59. PMC: 525433. DOI: 10.1128/AAC.48.11.4349-4359.2004. View

Zhang B, Zhang A, Chen L, Xi X . Inhibition of DNA helicase, ATPase and DNA-binding activities of E. coli RecQ helicase by chemotherapeutic agents. J Biochem. 2008; 143(6):773-9. DOI: 10.1093/jb/mvn026. View

Arai K, Yasuda S, Kornberg A . Mechanism of dnaB protein action. I. Crystallization and properties of dnaB protein, an essential replication protein in Escherichia coli. J Biol Chem. 1981; 256(10):5247-52. View

Shatalin K, Neyfakh A . Efficient gene inactivation in Bacillus anthracis. FEMS Microbiol Lett. 2005; 245(2):315-9. DOI: 10.1016/j.femsle.2005.03.029. View

10.

Biswas E, Biswas S . Mechanism of DnaB helicase of Escherichia coli: structural domains involved in ATP hydrolysis, DNA binding, and oligomerization. Biochemistry. 1999; 38(34):10919-28. DOI: 10.1021/bi990048t. View

11.

Zhi C, Long Z, Gambino J, Xu W, Brown N, Barnes M . Synthesis of substituted 6-anilinouracils and their inhibition of DNA polymerase IIIC and Gram-positive bacterial growth. J Med Chem. 2003; 46(13):2731-9. DOI: 10.1021/jm020591z. View

12.

Biswas E, Barnes M, Moir D, Biswas S . An essential DnaB helicase of Bacillus anthracis: identification, characterization, and mechanism of action. J Bacteriol. 2008; 191(1):249-60. PMC: 2612439. DOI: 10.1128/JB.01259-08. View

13.

Seefeld M, Miller W, Newlander K, BURGESS W, Payne D, Rittenhouse S . Inhibitors of bacterial enoyl acyl carrier protein reductase (FabI): 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as potential antibacterial agents. Bioorg Med Chem Lett. 2001; 11(17):2241-4. DOI: 10.1016/s0960-894x(01)00405-x. View

14.

Hooper D . Mechanisms of action of antimicrobials: focus on fluoroquinolones. Clin Infect Dis. 2001; 32 Suppl 1:S9-S15. DOI: 10.1086/319370. View

15.

Zhang , Chung , OLDENBURG . A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays. J Biomol Screen. 2000; 4(2):67-73. DOI: 10.1177/108705719900400206. View

16.

Love E, DAmbrosio D, Brown N . Mapping of the gene specifying DNA polymerase III of Bacillus subtilis. Mol Gen Genet. 1976; 144(3):313-21. DOI: 10.1007/BF00341730. View

17.

Appelbaum P, Hunter P . The fluoroquinolone antibacterials: past, present and future perspectives. Int J Antimicrob Agents. 2001; 16(1):5-15. DOI: 10.1016/s0924-8579(00)00192-8. View

18.

Bailey S, Eliason W, Steitz T . Structure of hexameric DnaB helicase and its complex with a domain of DnaG primase. Science. 2007; 318(5849):459-63. DOI: 10.1126/science.1147353. View

19.

Wei M, Wynn R, Hollis G, Liao B, Margulis A, Reid B . High-throughput determination of mode of inhibition in lead identification and optimization. J Biomol Screen. 2007; 12(2):220-8. DOI: 10.1177/1087057106296679. View

20.

Brown N, Wisseman 3rd C, Matsushita T . Inhibition of bacterial DNA replication by 6-(p-hydroxy-phenylazo)-uracil. Nat New Biol. 1972; 237(72):72-4. DOI: 10.1038/newbio237072a0. View